Circular RNA translation, a path to hidden proteome

Abstract

Functional proteins in the cell are translated from the messenger RNA (mRNA) molecules, constituting less than 5% of the cellular transcriptome.The majority of the RNA molecules in the cell are noncoding RNAs, including rRNA, tRNA, snRNA, piRNA, lncRNA, microRNA, and poorly characterized circular RNAs (circRNAs). Recent studies established that circRNAs regulate gene expression by associating with RNA-binding proteins and microRNAs.With the growing understanding of circRNA functions, a subset of circRNAs has been reported to translate into proteins. Interestingly, the presence of Open Reading Frames (ORFs), N6-methyladenosine (m6A) modifications, and internal ribosomal entry sites (IRES) in the circRNA sequences indicate their coding potential through the cap-independent translation initiation mechanism. The purpose of this review is to highlight the mechanism of circRNA translation and the importance of circRNA-encoded proteins (circ-proteins) in cellular physiology and pathology. Here, we discuss the computational and molecular methods currently utilized to systematically identify translatable cir-cRNAs and the functional characterization of the circ-proteins. We foresee that the ongoing and future studies on circRNA translation will uncover the hidden proteome and their therapeutic implications in human health. This article is categorized under:RNA Methods > RNA Analyses in Cells Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs Translation > MechanismsCircular RNAs (circRNAs) are a special class of covalently closed noncoding RNA molecules without the 5 0 and 3 0 ends. Initially, circular RNAs (circRNAs) were discovered to be uncoated, infectious RNA molecules pathogenic to plants (Sanger et al., 1976). Soon after their discovery, the expression of circRNA was also confirmed in eukaryotic cells (Hsu & Coca-Prados, 1979). A few subsequent studies discovered misarranged exons and circRNAs in various samples (Capel et al., 1993;Cocquerelle et al., 1993;Nigro et al., 1991). However, they were thought to be accidental byproducts arising from splicing errors until the next-generation sequencing (NGS) technologies were developed. Recent NGS and Tanvi Sinha, Chirag Panigrahi, and Debojyoti Das contributed equally to this study.

Identification of Potential circRNA-microRNA-mRNA Regulatory Network in Skeletal Muscle

“…circRNAs have been reported to regulate gene expression by acting as sponges for RNA-binding proteins (RBPs) and miRNAs ( Panda, 2018 ; Das et al, 2021 ). Also, a few circRNAs are translated into polypeptides with the cap-independent translation mechanisms, and some circRNAs regulate transcription by associating with snRNA and RNA pol II ( Bose and Ain, 2018 ; Sinha et al, 2021 ). CircRNAs are dynamically expressed and involved in various physiological processes, including development, differentiation, and aging ( Abdelmohsen et al, 2015 ; Di Timoteo et al, 2020 ).…”

Emerging Role and Mechanism of circRNAs in Pediatric Malignant Solid Tumors

“…Most circRNAs generated by reverse splicing are found mainly in the cytoplasm, and translation of linear mRNAs usually requires the structure of a 5′ end cap and a 3′ end poly(A) tail to remain stable. CircRNAs are not normally considered to have a translational function ( Marquez-Molins et al, 2021 ; Yan and Bu, 2021 ) but they can initiate translation in the cell if they have an internal ribosome entry site (IRES) ( He L. et al, 2021 ; Wang et al, 2021b ; Sinha et al, 2021 ). This approach provides more polypeptide sequences and increases the polypeptide yield because the ribosome does not need to bind to RNA template repeats ( Li P. et al, 2021 ).…”

Research Progress of circRNAs in Glioblastoma

“…In recent years, with the widespread application of transcriptomic gene sequencing and biophysical techniques, the biological functions of circRNAs and their roles in the development of human diseases are gradually being better understood with the help of high-throughput sequencing technologies. The circRNAs are mainly formed by processing protein-coding genes by RNA polymerase II( Ashwal-Fluss et al, 2014 ; Li et al, 2019 ; Ali et al, 2021 ; Sinha et al, 2021 ). Meanwhile circRNAs biosynthesis is mediated by RNA binding proteins, intron pair driven and lasso driven, and thus has an important role in regulating adjacent splice sites and promoting circular biosynthesis ( Wu et al, 2021a ; van Zonneveld et al, 2021 ; Zhao et al, 2021 ).…”